SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

Transcription

1 SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

2 SUMMARY OF SAFETY AND EFFECTIVENESS DATA I GENERAL INFORMATION Device Generic Name: Device Trade Name: Injectable Implant for Soft Tissue Augmentation Coaptite@ Applicant s Name and Address: BioForm Medical, Inc 1875 South Grant Street Suite 110 San Mateo, CA Date(s) of Panel Recommendations: None Pre-Market Approval Application (PMA) Number: PO40047 Date of Notice of Approval to the Applicant: November lo,2005 II INDICATIONS FOR USE COAPTITE@ is indicated for soft tissue augmentation in the treatment of stress urinary incontinence (SW) due to intrinsic sphincteric deficiency (ISD) in adult females Ill CONTRAINDICATIONS l In patients with significant history of urinary tract infections without resolution l In patients with current or acute conditions of cystitis or urethritis l In patients with fragile urethral mucosal lining IV WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the Coaptite@ labeling V DEVICE DESCRIPTION Coaptite@ is an injectable, sterile, non-pyrogenic implant composed of spherical particles of calcium hydroxylapatite (CaHA) ( microns in diameter:), suspended in an aqueous based gel carrier The gel carrier is composed of sodium carboxymethylcellulose, sterile water for injection, and glycerin The gel carrier suspends the CaHA particles, allowing their delivery through i,njection needles, and is dissipated in viva, while the CaHA particles remain at the injection sites to provide soft tissue augmentation lof19

3 CoaptiteB is, injected into the submucosal tissue of the urethra near the bladder neck The mechanism of action is to augment the surrounding soft tissue causing a coaptation of the urethra, increasing urethral resistance to the loss of urine The CaHA particles act as space-filling bulk for the urethral tissue VI ALTERNATE PRACTICES AND PROCEDURES Conventional procedures used in the treatment of female stress urinary incontinence include: behavioral techniques, such as bladder training and prompted voiding; pelvic floor strenqthening exercises (ie, Kenel exercises), with or without device assistance, such as biofeedback, vaginal cones, and electrical stimulation of the pelvic floor muscles; external devices, such as absorbent products (pads/diapers), collecting devices, or occluding devices; internal ulrethral occlusion devices; pharmacological treatments, such as alpha-adrenergic agonists and estrogen supplements; other iniectable bulking agents such as Contioen@ Durasphere and Urvx@ surgical treatments/procedures; such as suspension or sling procedures, and urinary diversion procedures VII MARKETING HISTORY CoaptiteB was approved (received CE mark) for the treatment of SUI in Europe in January 2001 CoaptiteB has not been withdrawn from any market for any reason VIII POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH The safety elf Coaptite@ for the treatment SUI is based upon a prospective, multicenter, single-blind study in which 158 Coaptite@ patients with SUI due to ISD were treated and evaluated through a 12-month period after initial treatment and compare,d to a control The Coaptite@ clinical study involved 307 CoaptiteB treatments in 158 subjects with a mean follow-up of approximately 112 months A total of 1265 adverse events were reported during the clinical study in 146 CoaptiteB (696 events) and 131 control patients (569 events) There were two treatment related serious adverse events in two patients in the CoaptiteB group A detailed discussion of the adverse events is presented in the Safety section In this section, only the serious adverse events and the genitourinary non-serious adverse events are discussed There were 33 serious adverse events in the study; 17 occurred in 11 Coaptite@ patients and 16 occurred in 12 control patients None of the 16 SAEs in the control group were considered treatment related Of the 17 SAEs in CoaptiteB 2of19

4 patients, two unanticipated SAEs (13%) were considered treatment related events involving dissection of CoaptiteB through the tissue l In one patient, erosion of approximately 1 cm on the vaginal wall just proximal to the m#eatus was observed Skin bridges extended between the erosion and the meatus The meatus was disconnected from the underlying fascia of the urethra such that the erosion extended from the bladder neck to the meatus In effect, vaginal wall overlying the urethra was no longer connected to the underlying structures and required corrective surgery l The 2 d patient with a history of pelvic surgery had failed her first bulking procedure with Coaptitea and underwent a 2 d bulking procedure Six months after the 2 d procedure, cystoscopy revealed CoaptiteB dissection into the bladder radially causing tissue bridges The right ureteral orifice was not visualized and follow-up ultrasound showed pelviectasis and caliectasis No corrective surgery was required There were no similar SAEs in the control group There was one reported death of a patient with lung cancer who was injected with CoaptiteB but it was determined not to be treatment related Table 1 presents details of the genitourinary NSAEs since these are the most relevant adverse events for urological procedures Table 1 Treatment Related Genito-urinary Non-Serious Adverse Events Iv % % Adverse Events reported for the CoaptiteB group were similar to those reported for the Control group Although not reported in the clinical study, other potential adverse events that may occur include erythema, embolic phenomena, and vascular occlusion 3of19

5 IX SUMMARY OF PRECLINICAL STUDIES Material Characterization and Performance Testing Testing of CoaptiteQ verified that the product met the required specifications regard to the following: in l CaHA particle size ( p) ph (74 :t 06) l X-ray Diffraction (typical of standard hydroxyapatite) l Extrusion Force (I 15 lb force with a 7 Fr x 35 cm and 21 gauge-needle) 0 Sterility Assurance Level of 10e6 l Pyrogen Level of -< 20 EWdevice Validation testing was completed on the components (calcium hydroxylapatite, sterile water for irrigation, and sodium carboxymethylcellulose) as well as on the final packaged and sterilized CoaptiteB The following bench tests were conducted to evaluate the performance characteristics of the final, packaged and sterilized CoaptiteB l Injection Testing - Coaptite@ can be extruded in one minute with an average force of approximately 98 pounds force (436 Newtons) l Syringe Leakage - Safety testing demonstrated that the syringe, injection needle or the syringe Luer cap would not rupture with the maximum hand pressure of 30 pounds force (133 Newtons) applied to the syringe push rod using the finger grips l Simulated Use Testing - CoaptiteQ as prepared for injection in primed injection needles, remained functional after twelve hours at room temperature conditions showing that its injectability is not affected by potential water loss l Particle IDurability - The particles of calcium hydroxylapatite remained unchanged (no significant change in particle size distribution) after 3-4 years of implantation in dogs, demonstrating that the particles are durable Sterilization and Shelf-life Testing Steam sterilization of Coaptite@-filled 1 cc syringes was validated to provide a sterility assurance level (SAL) of 104 Testing performed on the finished product verified that endotoxin levels were consistently maintained The heat-sealing of the foil pouches has been validated and demonstrated to produce consistent seals with peel strengths of 5 pounds force Real time and accelerated testing (at 45 C) on Coaptite@ confirmed sterility and product functionality for a shelf-life of 36 months These studies included simulation of shipping and handling conditions Biocompatibility Testing In vitro and,in viva tests were based on IS (Biological Evaluation of Medical Devices), using accepted test methods of biomedical materials or United States Pharmacopoeia references These studies were conducted under 4of19

6 Good Laboratory Practice (GLP) guidelines In vitro tests were performed to investigate cytotoxicity, blood interactions, and mutagenic responses The test results indicated CoaptiteB is nontoxic, non-sensitizing and non-mutagenic Although CoaptiteB was found to be hemolytic during testing, the hemolysis was attributed to the glycerin (a known hemolytic agent) found in the aqueous gel vehicle The 36-month dog study and the clinical study discussed below have not reported any findings of clinical significance from this potential hemolytic reaction Table 2 lists the various biocompatibility tests conducted and the results Table 2 Biocompatibility Test Results Results Non-Toxic Non-Toxic Non-Antiaenic Non-Irritant Non-Irritant Non-Toxic Non-Mutagenic No Significant Effect 1 Hemolysis Hemolytic - Animal Studies: 36-month Dog Study A 36-month implant study was conducted with CoaptiteB in dogs The objective of the study was to determine the tissue compatibility and migration potential of Coaptite@ Using cystoscopic guidance, Coaptite@ was injected into the periurethral tissue of the bladder neck in twenty-four (24) female dogs, Twelve (12) additional dogs were similarly injected with the gel carrier (CoaptiteQ without the calcium hydroxylapatite particles) Dogs assigned to the 12, 24 and 36-month groups were re-injected six months after the initial injection Blood and urine samples were collected from each animal for routine hematology, clinical chemistry and urinalysis prior to study initiation, at six month intervals, and prior to termination Designated dogs were terminated at 1, 3, 6, 12, 25 and 36 months after initial injection Each was necropsied; injection sites and other tissue inspected grossly; and implant sites and selected tissues processed for microscopic examination All of the dogs tolerated the procedure well and remained in good health during the course of the study except one that was euthanized for a reason unrelated to the Coaptite@ implantation The dog study reported the following significant findings: l The hematology, clinical chemistry, urinalysis were acceptable throughout the study All findings noted during necropsy were found to be within normal limits There was no clinical evidence that the injection procedure or the Coaptite@ caused untoward effects in the dogs 5of19

7 Microscopic evaluations of the implant sites at 1, 3, 6 and 12 months revealed two mixed but separate responses A simple macrophage clearing response was associated with the sodium carboxymethylcellulose in the gel carrier of the CoaptiteB Most of the gel carrier disappeared at the 6-month time point A delicate fibrous encapsulation was associated with the CaHA particles at all time points (3, 6, 12, 24 and 36 months) The CoaptiteB at all time points was found as a well-defined injection site The CaHA particles and the carrier remained at the injection site with no evidence of free migration Some CaHA particles were found in distant tissues but this was considerled an injection accident, not the result of migration The accidental deposits of CaHA particles found in non-injection tissues resulted in no clinical response While a small amount of CaHA had undergone degradation into small particles (< 10 p size) at the 24- and 36-month time points and were engulfed and solubilized at the site by macrophages, most remained intact Published literature on hydroxyapatite indicates that the breakdown into smaller particles occurs at the grain (fusion) boundaries of hydroxyapatite The degradation into smaller particles and phagocytosis was similar to the degradation of hydroxyapatite implants used in the correction of bone defects The CaHA particles engulfed by macrophages are cleared by reticuloendothelial system like any other foreign material of small size Because of the degradation of CaHA particles into smaller size particles after 12 months of implantation, the macrophage response is expected to continue beyond the 36-month period until all CaHA is degraded into small particles and solubilized It was concluded from the biocompatibility testing and the dog study that CoaptiteO is safe for injection into urinary bladder sites (urethral submucosa) X SUMMARY OF CLINICAL STUDIES Study Design The study was a prospective, randomized, comparative, single blind, parallelgroup, multi-center clinical trial of Coaptite@ and Control in female patients for soft tissue augmentation of the urethral sphincter with stress urinary incontinence (SUI) due ts intrinsic sphincter deficiency (ISD), ie, leak point pressure I 100 cm H20 and without associated urethral hypermobility as defined by resting or straining angle of I 35 from horizontal of the bladder neck Fourteen sites in the USA enrolled and treated the patients Five hundred forty five (545) patients were randomized after signing the informed consent Patients were then screened to determine if they met the eligibility criteria (inclusion/exclusion) and passed the skin sensitization test Two-hundred forty-nine (249) patients did not receive injections as they failed one or more of the screening tests, withdrew consent or for other reasons Because randomization of the patients occurred before patient eligibility for treatment was determined, a true 1:l distribution was not achieved, with slightly more patients receiving CoaptiteB (158) than those receiving the Control (138) Protocol deviations occurred in 45 patients and were distributed equally between the two groups (23 CoaptiteQ and 22 Control) 6of19

8 All injections were performed by the investigators Evaluations (baseline and post-procedure) that affected the efficacy variables and safety profile as defined in the protocol were performed by or under the direction of the investigator at each site Objective The objective was to evaluate the safety and effectiven,ess of Coaptitea compared with the Control The effectiveness evaluation was based on improvement on the Stamey Urinary Incontinence Scale (Stamey Grade) The safety evaluation was based on adverse events, physical examination, and laboratory test results Primary Effectiveness Endpoint The primary effectiveness of as compared to the Control was measured by at least a one-grade improvement at 12 months after initial injection treatment over the baseline measurement of the Stamey Urinary Incontinence Scale The method used to evaluate the level of continence in the study was first defined by Stamey2 in 1979 and is considered one of the standard scales to be used for these types of evaluations The Stamey Scale has been used in previous clinical studies for other approved tissue bulking materials for the treatment of urinary incontinence The grades within the Stamey Scale are defined as: Grade 0: Continent (dry) Grade 1: Urine leakage is associated with vigorous activities such as lifting weights, coughing or sneezing, but never in bed at night Grade 2: Urine leakage is associated with activities of minimal stress, such as walking or standing up Grade 3: Urine leakage occurs at all times regardless of activity or position Secondarv Effectiveness Endpoints In addition to Stamey Grade the following additional effectiveness endpoints were collected: l Cure ratle at 12 months using Stamey Grade, defined as the number of patients that were dry at 12 months (Grade 0) l Significant improvement at 12 months using Stamey Grade, defined as a decrease in 2 or more grades at 12 months from baseline l Improvement in pad weight at 12 months using a 24-hour pad weight test, defined as a decrease of at least 50% in pad weight from baseline l Improvement in quality of life at 12 months using incontinence quality of life questionnaire (I-QOL), defined as mean improvement at 12 months from baseline Safetv Endpoints The safety assessment was defined as an acceptable safety and tolerability profile This included evaluation of the incidence of treatment-related adverse 7of19

9 events by :,everity and causality, and detailed presentation of genitourinary adverse events Patient Selection Inclusion criteria were: Female patients with urinary stress incontinence due to intrinsic sphincteric deficiency (leak point pressure cm H20) and without associated urethral hypermobility (as defined by resting or straining angle of 535 from horizontal of the bladder neck) Patients at least 18 years of age Patient s continence had not shown any improvement in the last six months l 0 Patient had failed prior noninvasive treatments (eg, behavior modification, bladder exercises, biofeedback, electrical stimulation and/or drug therapy) Patient had good bladder function and a healthy bladder (bladder capacity greater than 250 ml and absence of detrusor instability) Patient had viable mucosal lining at likely site of injection (bladder neck) Patient had a negative urine culture as defined by midstream sample with an organism count of less than 10,000 and with no history of infection within a month of injection Patient was mentally competent and able to understand all study requirements Patient had a life expectancy of at least two years Patient agreed to be available for the follow-up evaluations as required by the protocol Patients who were willing to provide witnessed informed consent and who were willing and able to participate in all procedures and follow-up evaluation necessary to complete the study The exclusion criteria were: Patient had vesicoureteral reflux, spastic bladder, detrusor instability, or high pressure instability Patient was on current medication for urinary incontinence Patient had urinary incontinence for neurogenic etiology Patient had current or acute conditions involving cystitis or urethritis Patient used indwelling catheters for a long period of time and had fibrosis of the tissue at the likely injection sites Patient had received pelvic radiotherapy and had fibrosis of the tissue at the likely injection sites Patient was pregnant, lactating, or planning to become pregnant in the next twelve months Patient had any condition which could lead to significant post operative complications, including current infection, uncontrolled diabetes, or elevated residual urine from bladder outlet obstruction Patient had previous treatment of urinary incontinence with a urethral bulking agent Patient had urinary incontinence primarily due to detrusor dysfunction (defined as detrusor insufficiency or detrusor hyperreflexia with detrusor contraction greater than 20 cm of water) associated with neurogenic illness or detrusor insufficiency with overflow incontinence 8of19

10 Patient had bladder capacity of less than 250 ml or post void residual volume of more than 50 ml Patient was taking medication(s) primarily prescribed to affect urinary physiology (ie, anticholinergic, adrenergic) Patient could be enrolled if drug(s) was discontinued and a wash out period of four weeks was observed prior to baseline testing Patient vvas morbidly obese (defined as 100 pounds over their ideal body weight according to Metropolitan Life Insurance Company tables) and would not be expected to benefit from treatment Patient with very short urethra and multiple urethral surgeries for stress incontinence who was not a candidate for injection treatment based upon the investigator s discretion Patient had any condition that would preclude anesthesia or treatment due to contraindications and/or warnings in the experimental or control product labeling Patient was actively immunosuppressed or allergic to bovine collagen product and/or lidocaine or had a positive reaction in the Control article skin test or was undergoing or intended to undergo desensitization injections to meat products Statistical Considerations Coaptite@ was considered non-inferior to the control if a 95% confidence interval (Cl) for the Idifference in the primary efficacy variable was contained within the bounds of 15% of the control group proportion The patients in the control group were expected to have primary efficacy variable success rate of 70% One hundred sixteen (116) patients per treatment group were required to achieve 15% bound of the two-sided 95% Cl for the difference with an alpha = 005 and power = 80% (PI = P2 =70%), provided that the primary efficacy variable in the control group is 70% This means that 232 patients were required to have 12- month follow-up Assuming a 20% drop out rate and 1 :I randomization to the two treatment groups, 280 patients needed to be treated and followed for 12 months Treatment Patients that did not demonstrate a response to the skin test and who were otherwise eligible for treatment were treated A treatment was defined as one or more injections of Coaptite@ or the Control That is, injections at one or more tissue sites iin the urethra in one treatment session Soft tissue augmentation of the urethral sphincter was performed under anesthesia and with cystoscopic guidance The anesthesia type and the route of injection were at the discretion of the investigator The maximum total volume of Coaptite@ that could be injected during one treatment session was fifteen (15) ml The maximum number of treatments was limited to five (5) per patient If a satisfactory improvement was not achieved after the initial treatment, additional injection procedures were allowed during the first six months after the initial injection if the investigator determined that it was necessary The additional injection procedures were to be scheduled a minimum of seven days from the previous procedure 9of19

11 Follow-up Examination Schedule All patients (CoaptiteB and Control) were scheduled for follow-up examinations at 1, 3, 6, 9 and 12 months after the initial injection, with 48 Coaptite@ patients followed for 24 months Data collected at those examinations included physical examination, hypermobility assessment, uroflowmetry, urinalysis, cystometry, post cystometry pad test, 24-hour pad test, cystoscopic examination, quality of life, pelvic x-ray, voiding dairies laboratory tests, and Stamey scale rating Data Collection During the baseline and follow-up visits, patient and medical history data relevant to the diagnosis of SUI, and data from laboratory testing, pad weight testing, voiding diaries and a quality of life (IQOL) assessment were collected In addition to the assessment in changes in continence grades, data were also recorded on treatment related symptoms and adverse events Demographic Data and Baseline Data Patients that received CoaptiteB were adult females with an average age of 61 years Table 3 presents the demographics and Table 4 presents baseline characteristics of the study population There was no difference in the two patient groups for any of the patient demographics and/or baseline characteristics Table 3 Patient Demographics and Baseline Characteristics Characteristic Coaptite@ Control p-value Age W-s) N Mean Std Dev Median Min Max Urethral Length (cm) N Mean Std Dev Median Min Max Incontinence Type N 158 ~ I Stress Mixed 1 I 27 I~ Duration of N Incontinence Mean (Months) Std Dev I Median I n L I Min t Max Previous Treatments N Surgery 61 (386%) 48 (348%) Medication 51 (323%) 46 (333%) loof

12 Charac Post Void Residual (ml) Leak Point Pressur (cm W) Race Table 4 Patient Baseline Profile /- COAPTITEB 1 Control Mean Age in Years (F!ange) Mean Duration of Incontinence in years (Range) Mean Baseline Stamey Grade (Range) Patients With Baseline Stamey = 1 (%) Patients With Baseline Stamey = 2 (%) Patients With Baseline Stamey = 3 (%) 24 (l52%) 18 (i31%) 59 (373%) 36 (263%) 75 (475%) 83 (606%) 748 ( ) 853 ( ) 429 (30-900) 453 (20-880) Treatment Information Of the 296 patients receiving treatment, Stamey Grade evaluation at baseline as well as at the twelve-month period was available for 231 (131 Coaptite@ and 100 Control) patients Table 5 summarizes the treatment related data for the patients in both the Coaptite@ and Control arms of the clinical study A majority of the Coaptite@ and Control patients received more than one injection It was not uncommon for a 2nd and 3rd injection in both groups Table 5 Treatment Information for Patients followed for 12 Months r Treatment Information Coaptite@ Control N =I31 N=lOO (374%) 27 (270%) 51 (389%) 53 (530%) 23 (176%) 15 (150%) 8 (61%) 5 (50%) 11 of19

13 Treatment InformatIon 1 Mean time betweerl treatments (months) per patient (ml) per patient (ml) 1 Coaptitea 1 Control _-- N=131 N= 100 I 28 (06-120) 27 (07-65) 22 (05-45) 33 (1 o - 75) 40(10-110) 68 (15-195) Effectiveness Results Primary Effectiveness The primary endpoint was to determine if Coaptite@ was non-inferior to the Control in terms of the proportion of patients who experienced improvement (at least a one,grade improvement on the Stamey Scale) and were able to maintain it twelve months after the initial injection treatment As shown in Table 6, there was no significant difference between Coaptite@ and Control groups Out of the 158 patients treated with CoaptiteB, 91 improved and 15 had worsening of their incontinence It was unclear whether the remaining 52 patients had any improvement from baseline Table 6 Intent-to-Treat (LOCF) 12-Month Effectiveness Results EFFECTIVENESS at 12 MIONTHS Substantially improved (2 2 grade decreasl, lmbrovement II \ 1 Y----- arade decrease) I 91 (576%) 70 (507%) Worsening 15 (95%) 10 (72%) PAD WEIGHT Dry 150% improvement 37 (282%) 31 (310%) (513%) 53 (384%) 149% improvement 12 (75%) 9 (65%) Worsening or no improvement from Baseline 65 (411%) 76 (551%) IQOL Mean improvement (range) (-41 O ) ( O) I- ~~ -- Table 7 presents the effectiveness results for patients that completed the study This table shows that, of the 131 CoaptiteB treated patients who had 12-month Stamey Grade follow-up, 83 had improved and 13 had worsening of their incontinence from baseline It is unclear whether the remaining 35 patients had any improvement in their incontinence 12of19

14 EFFECTIVENESS Table 7 12-Month Effectiveness Results for Pts with Complete 12- month Data at 12 MONTHS STAMEY GRADE Dry (Grade 0) Substantially improved (1 2 grade decrease) Improvement (1 1 grade decrease) Worsening or no improvement from Baseline PAD WEIGHT Dry 2 50% improvement l-49% improvement Worsening or no improvement from Baseline IQOL Mean improvement (range) CoaptiteB Control p-value N=131 N=lOO 51 (389%) 37 (370%) (504%) 46 (460%) (634%) 57 (570%) (99%) fi (60%) N=131 N = (282%) 31 (310%) (618%) 53 (535%) 12 (92%) 9 (91%) (290%) 37 (374%) N = 123 N= (-41 O ) ( QlO) Table 8 provides effectiveness patients received data with respect to the number of treatments Table 8 Injection Results for the 12-month Completed Study Effectiveness Results with respect to single vs Coaptite@ Control N=131 N=lOO Improved at 12 months with single treatment (674%) (778%) Cured at 12 months with single treatment 27/49 (551%) 17/27 (630%) Improved at 12 months with multiple treatments 50/82 (61 O%) 36/73 (493%) 1 Cured at 12 months awith multiple treatments (293%) 1 20/73 (274%) The route of injection, transurethral or periurethral, was at the discretion of the investigator Table 9 provides details about the number of patients treated with transurethral or periurethral injection methods Transurethral method was used in 92% of the Coaptite@ patients and 89% of the control patients There were insufficient numbers of patients treated by the periurethral method to determine the safety and effectiveness of this injection route for Coaptite@ Table 9 Initial Route of Injection Coaptite@ Control Transurethral 145 (918%) 123 (891%) 13 (82%) 15 (109%) p-value Secondarv Effectiveness Results Coaptite@ was found to be not significantly different (p = 07860) to the Control in the proportion of patients who achieve and maintain a complete cure (Stamey Grade = 0) twelve months after the initial injection treatment (389% vs 370%, respectively) 13of19

15 The proportion of CoaptiteB patients who achieved and maintained substantial improvemem (at least a two grade change &r to Grade 0 at 12 months) was similar (p = 05952) to the Control patients (504% vs 460%, respectively) There was no significant difference (p = 02259) between CoaptiteB patients that had at least a 50% decrease in pad weight at 12 months when compared to the Control patients (618% vs 535%, respectively) Patients were asked to complete an Incontinence Quality of Life Assessment (I- QOL) The results revealed that the patient s improvement in the-quality of life score was similar for both groups (p = 01340) at the 12 month follow-up period when compared to the baseline score Coaptite@ demonstrated a significant improvement (p c 00001) in the quality of life score at 12 months when compared to the baseline score (see Table 10) Table IO Improvement in Quality of Life from Baseline at 12 Months Category Coaptite@ p-value N =I23 Overall 311 < Avoidance and Limiting Behavior 313 c Psychosocial Impacts 276 < Social Embarrassment 359 < Safety Results All Adverse Eivents Observed through 12 months Safety of Coaptite@ treatment was monitored by recording all adverse events (serious as well as non-serious) in the case report forms (CRFs) The CRF solicited a description of the event, start and stop dates, and its intensity, frequency, treatment, causality, and outcome As expected, several patients were reported to have experienced adverse events in both Coaptite@ and Control groups The adverse event information reported included all the 158 Coaptitea treated patieints and 138 Control treated patients Overall, a total of 1265 adverse events were reported in both groups A total of 696 adverse events were reported during the study in the Coaptite@ group, 17 serious adverse events (SAEs) and 679 non-serious adverse events (NSAEs) SoNme of the patients had both SAEs and NSAEs In comparison, the control device had a total of 569 adverse events in 138 patients, 16 SAEs and 553 NSAEs All the 16 SAEs in the control group occurred in 12 patients and were considered not related to the treatment (device or procedure) Only the NSAEs are discussd below See Section VIII (Potential Adverse Effects) for a discussion of SAEs The patients in the CoaptiteB and Control groups who had experienced the NSAEs (679 events in the CoaptiteB group and 553 events in the Control group) are shown in Table 11, organized by the adverse event category The 679 NSAEs in the CoaptiteB group was the sum of both Treatment Related and Not Treatment Related NSAEs This table presents the number of patients who experienced at least one NSAE 14of19

16 , Table 11 Total Non-Serious Adverse Events-lncidences and Patients I Incidence I Patients EVENT CoaptiteB Control p- CoaptiteB Control N=158 N = 138 value RENAUGENITOURINARY (658%) 91 (65 9%) 1 0 I I I I I - INFECTION, URINARY I (;91%) 135 (254%)1 051 r- i ;; ;j i 30 i19o%j 23 il6 7%j (171%) 21 (152%) 075 SEXUAL/REPRODUCTIVE FUNCTION WIARY ii33%j (120%) 20 (145%) i145%j DERMATOLOGY/SKIN METABOLIWABORAT SURGERY/INTRA-OPE LYMPHATICS NEUROLOGY PULMONARY/UPPER F VASCULAR ALLERGY/IMMUNOLO( BLOOD/BONE MARRO ENDOCRINE CARDIAC GENERAL CARDIAC ARRHYHMIA OCULARNISUAL AUDITORY/EAR HEPATOBILIARY/PANC TOTAL Non-Serious Adverse Eve The p-values provided in Table 11 show that the number of patients who experienced the NSAEs in each adverse event category was similar in both CoaptiteO and Control groups and there is no statistically significant difference between the two groups Although there are additional potential risks with bulking agents identified in the literature, including hardening of the tissues at the injection site and/or allergic or autoimmune reactions, these were not reported in any patients Treatment Related Adverse Events Of the 679 total NSAEs in the Coaptite@ group, 334 NSAEs were determined to be treatment related They occurred in 137 Coaptite@ patients The correspondirlg number of treatment related NSAEs in the Control group were 257 The criteria used for determining that an adverse event was related to the treatment are described on the following page: 15of19

17 l NSAE occurring 0 to 7 days after any injection, l NSAE occurring >7days after any injection and considered definitely related to the injection, l NSAE occurring > 7 days after any injection and considered probably related to the injection, l NSAE occurring > 7 days after any injection and unknown if it was related to the injection These were conservative criteria for determining whether a NSAE was treatment related Ta,ble 12 presents the number of treatment related incidence and patients in both treatment groups with a NSAE in each adverse event category Table 12 Treatment Related Non-Serious Adverse Events-Incidence and Patie nts REN*uGENITo~~~~ 1 P- I PAIN URlNARY INFECTION, URINARY (89%) 14 ilol%j SURGERY/INTRA-OPERATIVE INJURY ((70%) 6(43%) SEXUAL/REPRODUCTIVE FUNCTION (63%) 8 (58%) GASTROINTESTINAL % (63%) 6 (43%) ENDOCRINE (Ooo/o) 1 (07%) PULMONARY/UPPER RESPIRATORY (00%) 3 (22%) OCULAR/VISUAL (00%) 2(15%) CARDIAC GENERAL (00%) 1 (07%) AUDITORY/EAR (00%) 0 (00%) HEPATOBILIARYIPANCREAS (00%) 0 (00%) TOTAL Non-Serious Adverse Events (639%) 91 (659%) oooo N/A 1 oooo N/A N/A N/A N/A N/A N/A N/A N/A The table shows that the Coaptite@ and Control groups had similar rates of treatment related adverse events in each adverse event category and there was no statistically significant difference between the two groups Coaptitea group had no allergic or immunologic reactions while 3 patients had allergic reactions in the Contigen group Urinary tract infection (UTI), a common occurrence with urological procedures, occurred in both CoaptiteB and Control groups at the 16of19

18 same rate Thirteen (13) CoaptiteB patients had 18 UTls as compared to 14 Control patients with 24 UTls Urinary retention had the highest rate among the genitourinary NSAEs Forty one percent (41%) of the CoaptiteB patients and 33% of Control patients had urinary retention related to the treatment Retention is followed by hematuria (196%) and dysuria (15O/;,) in CoaptiteB patients Most treatment related adverse events occurred within 24 hours of treatment and subsequently resolved within 30 days At the time of database closure, 91% of treatment related adverse events were resolved The following treatment related urinary related events were persistent or resolution was unconfirmed at the time of database closure (the number of events is shown in parentheses): Urge incontinence (5); micturition urgency (3); hypertonic bladder (2); urinary retention (2); urethral disorder (2); and one event each of back pain, bladder spasm, dysuria, injection site reaction, mucosal erosion, edema peripheral, urinary tract obstruction With respect to severity of the 334 treatment related adverse events in the CoaptiteB group: l 232 (69:5%) were rated as mild; l 92 (276%) were rated as moderate; and l 10 (30%) were rated as severe Adverse Events Reported Between 12 and 24 Month Follow-up A total of 11 adverse events were reported between 12 and 24 months for the 48 COAPTITE@ patients seen through 24 months One serious adverse event was reported (bladder cancer) and determined not to be related to either the procedure or the device The remaining non-serious adverse events reported between 12 and 24 months include hematuria (l), inflamed introitus (I), anterior bladder neck swelling (1) urinary tract infection (4), urge incontinence (?), bladder erythema (1) and burning on urination (1) Xl CONCLUSIONS The preclinical data provided, adequately characterize the device s materials, justify a 3-year shelf life and demonstrate that CoaptiteB is safe for long-term implantation in the urethral submucosa The results of the study on all treated patients (158 in CoaptiteB group and 138 in the Control group) demonstrate that 34% of the CoaptiteQ patients were dry and 576% were improved by Stamey Grade assessment In comparison, 30% of the Control patients achieved dryness and 51% achieved improvement Using the criteria of 24-hour pad weight results, 28% achieved dryness and 51% achieved improvement (150% decrease in urine loss after treatment) in the CoaptiteB group Comparative cure and improvement rates were 31% and 38% respectively for the Control The statistical analyses (p-values) clearly demonstrate that Coaptitea is noninferior to the Control for soft tissue augmentation for the treatment of SUI The quality of life for all patients (both CoaptiteB and Control patients) revealed a 17of19

19 significant improvement when comparing the 12-month scores to the baseline scores There were 1~0 unanticipated, treatment related, serious adverse effects in the CoaptiteB group These SAEs involved dissection of the device through tissue resulting in tissue bridges and erosion Upon review of these events, it could not be concluded whether they were directly attributable to the device; the events were believed to be more likely the result of poor injection technique Another consideration is that peripheral vascular disease and prior pelvic surgery could have contributed to the tissue erosion The boxed warnings in the physician labeling (Instructions for Use) are intended to alert the physicians to the consequences of a poor injection technique and improper patient selection, and minimize the chances of occurrence of similar types of adverse events in the future The postmarket enhanced surveillance and postapproval study requirements are intended to help identify the cause of these adverse events, should they occur again With regard to anticipated adverse effects Coaptitee had a safety profile similar to that of the Control Furthermore, Coaptitee did not have any incidence of treatment related allergic reactions as compared to the Control which had allergic cases None of the subjects experienced prolonged retention, obstruction, nor complaints of prolonged pain, discomfort, or inflammation in the area of the implant were reported There were no clinically significant laboratory findings that indicated Coaptitee exhibited any systemic effects It has been concluded that CoaptiteB is safe and effective for its intended use of soft tissue augmentation of the urethral sphincter in the treatment of stress urinary incontinence when it is used in accordance with the Instructions for Use XII PANEL RECOMMENDATIONS In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the Gastroenterology and Urology Devices Advisory Panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel XIII CDRH DECISION CDRH has reviewed the two serious, treatment related adverse events in CoaptiteQ3 injected patients and required boxed warnings to alert physicians to the potential occurrence of similar events in the future This step for physician awareness is intended to help minimize the incidence of this type of adverse event when CoaptiteO is marketed One of the conditions of approval is a 2-year enhanced postmarket surveillance program that requires the company to actively solicit the adverse event information related to the use of CoaptiteB This requirement would help in documenting the rate of occurrence of similar serious adverse events Another requirement, a 5year postapproval study, would help in establishinlg the causality of these serious adverse events, if they occur in the future 18of19

20 Based upon its review of the PMA, CDRH concludes that these data, the labeling requirements and postapproval requirements provide a reasonable assurance that Coaptitee is safe and effective when used in accordance with the Instructions for Use FDA issued an approval order on November IO,2005 The applicants manufacturing facility was inspected on June 14-17, 2004, and was found to be in compliance with the Quality System Regulation (21 CFR 820) XIV APPROVAL SPECIFICATIONS Instructions for Use: See the labeling Hazards to Health from Use of the Device: See Indications, Warnings, Precautions and Adverse Events in the labeling Contraindications, xv Post-approval Requirements and Restrictions: See approval order REFERENCES - 1 Use of International Standard IS , Biological Evaluation of Medical Devices, Part I: Evaluation and Testing FDA, CDRH, May 1, Stamey T Urinary Incontinence in the Female: In Campbell s Uroloqy Fourth Edition Philadelphia WB Saunders Company pp of 19